Structure and function of enterotoxigenic <scp><i>E</i></scp><i>scherichia coli</i> fimbriae from differing assembly pathways

Mortezaei, Narges; Epler, Chelsea R.; Shao, Paul; Shirdel, Mariam; Singh, Bhupender; McVeigh, Annette L.; Uhlin, Bernt Eric; Savarino, Stephen J.; Andersson, Magnus; Bullitt, Esther

doi:10.1111/mmi.12847

Cited by 26 publications

(34 citation statements)

References 52 publications

(77 reference statements)

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“…ETEC fimbriae such as CS2, CFA/I, and CS20 require <15 pN unwinding force, despite differences in their assembly mechanism (see Table S1 and our previous work (24,26)); UPEC and meningitis-associated strains of E. coli express fimbriae requiring 21-30 pN of unwinding force (33,39,42); however, Type 3 fimbriae expressed by K. pneumonia in the respiratory tract require 66 pN of unwinding force (43). One should also note that the T4 fimbriae expressed by Streptococcus pneumonia, which also colonize the respiratory tract, are significantly stiffer than UPEC-and ETEC-expressed fimbriae (45).…”

Section: Discussionmentioning

confidence: 96%

“…Interestingly, fimbriae expressed in a specific microenvironment exhibit similar properties; for example, the unwinding force of CS20 is more similar to that of CFA/I than to that of P fimbriae, even though CS20 antigens share higher amino acid identity with the pilins of P fimbriae (26). Thus, the structural and biomechanical characteristics of fimbriae appear to play a determinant role in E. coli colonization and pathogenesis in a specific organ, i.e., E. coli strains sharing a common niche express fimbriae with similar biophysical properties (26).…”

Section: Introductionmentioning

confidence: 94%

“…Thus, the structural and biomechanical characteristics of fimbriae appear to play a determinant role in E. coli colonization and pathogenesis in a specific organ, i.e., E. coli strains sharing a common niche express fimbriae with similar biophysical properties (26). ETEC-expressing CS2 fimbriae are known to localize to the small intestine, an environment similar to that of ETEC-expressing CFA/I fimbriae of the ACP family and CS20 fimbriae of the CUP.…”

Section: Introductionmentioning

confidence: 97%

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Biomechanical and Structural Features of CS2 Fimbriae of Enterotoxigenic Escherichia coli

Mortezaei

Singh

Zakrisson

et al. 2015

Biophysical Journal

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Enterotoxigenic Escherichia coli (ETEC) are a major cause of diarrhea worldwide, and infection of children in under-developed countries often leads to high mortality rates. Isolated ETEC expresses a plethora of colonization factors (fimbriae/pili), of which CFA/I and CFA/II, which are assembled via the alternate chaperone pathway (ACP), are among the most common. Fimbriae are filamentous structures whose shafts are primarily composed of helically arranged single pilin-protein subunits, with a unique biomechanical ability to unwind and rewind. A sustained ETEC infection, under adverse conditions of dynamic shear forces, is primarily attributed to this biomechanical feature of ETEC fimbriae. Recent understanding about the role of fimbriae as virulence factors points to an evolutionary adaptation of their structural and biomechanical features. In this work, we investigated the biophysical properties of CS2 fimbriae from the CFA/II group. Homology modeling of its major structural subunit, CotA, reveals structural clues related to the niche in which they are expressed. Using optical-tweezers force spectroscopy, we found that CS2 fimbriae unwind at a constant force of 10 pN and have a corner velocity (i.e., the velocity at which the force required for unwinding rises exponentially with increased speed) of 1300 nm/s. The biophysical properties of CS2 fimbriae assessed in this work classify them into a low-force unwinding group of fimbriae together with the CFA/I and CS20 fimbriae expressed by ETEC strains. The three fimbriae are expressed by ETEC, colonize in similar gut environments, and exhibit similar biophysical features, but differ in their biogenesis. Our observation suggests that the environment has a strong impact on the biophysical characteristics of fimbriae expressed by ETEC.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 97%

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Biomechanical and Structural Features of CS2 Fimbriae of Enterotoxigenic Escherichia coli

Mortezaei

Singh

Zakrisson

et al. 2015

Biophysical Journal

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“…The model is also consistent with an axial hole (~ 2 nm), which is only visible on the electron micrograph of thicker fimbriae. Thick helical fimbriae can be stretched under certain in vitro conditions (117) or by using force to unwind the helix (118), accompanied by conformational changes in fimbrial subunits. It has been suggested that fimbrial stretching occurs in vivo to adjust and coordinate the lengths of the few hundred fimbrial threads anchoring the colonizing bacteria that are submitted to the intestinal peristalsis and its resulting shear force (119).…”

Section: Fimbrial Structuresmentioning

confidence: 99%

Animal EnterotoxigenicEscherichia coli

2016

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Enterotoxigenic Escherichia coli (ETEC) is the most common cause of E. coli diarrhea in farm animals. ETEC are characterized by the ability to produce two types of virulence factors; adhesins that promote binding to specific enterocyte receptors for intestinal colonization and enterotoxins responsible for fluid secretion. The best-characterized adhesins are expressed in the context of fimbriae, such as the F4 (also designated K88), F5 (K99), F6 (987P), F17 and F18 fimbriae. Once established in the animal small intestine, ETEC produces enterotoxin(s) that lead to diarrhea. The enterotoxins belong to two major classes; heat-labile toxin that consist of one active and five binding subunits (LT), and heat-stable toxins that are small polypeptides (STa, STb, and EAST1). This chapter describes the disease and pathogenesis of animal ETEC, the corresponding virulence genes and protein products of these bacteria, their regulation and targets in animal hosts, as well as mechanisms of action. Furthermore, vaccines, inhibitors, probiotics and the identification of potential new targets identified by genomics are presented in the context of animal ETEC.

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“…Recent studies suggest that the quaternary structure of a fimbrial shaft plays an additional deterministic role in colonization, inasmuch as the shaft of certain ETEC fimbriae, as well as those of other pathogenic E. coli, is adapted to organ-specific biomechanical and structural features. Despite their differences in biogenesis and assembly processes, when analyzed biomechanically, ETEC-expressed fimbriae unwind at a characteristic low-unwinding steady force of Ͻ20 pN (7,8), while fimbriae expressed by extraintestinal pathogenic E. coli (ExPEC), such as type 1, P, and S fimbriae, require a steady force of Ͼ20 pN to unwind (7,(9)(10)(11)(12).…”

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confidence: 99%

Antibodies Damage the Resilience of Fimbriae, Causing Them To Be Stiff and Tangled

et al. 2017

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As adhesion fimbriae are a major virulence factor for many pathogenic Gram-negative bacteria, they are also potential targets for antibodies. Fimbriae are commonly required for initiating the colonization that leads to disease, and their success as adhesion organelles lies in their ability to both initiate and sustain bacterial attachment to epithelial cells. The ability of fimbriae to unwind and rewind their helical filaments presumably reduces their detachment from tissue surfaces with the shear forces that accompany significant fluid flow. Therefore, the disruption of functional fimbriae by inhibiting this resilience should have high potential for use as a vaccine to prevent disease. In this study, we show that two characteristic biomechanical features of fimbrial resilience, namely, the extension force and the extension length, are significantly altered by the binding of antibodies to fimbriae. The fimbriae that were studied are normally expressed on enterotoxigenic Escherichia coli, which are a major cause of diarrheal disease. This alteration in biomechanical properties was observed with bivalent polyclonal antifimbrial antibodies that recognize major pilin subunits but not with the Fab fragments of these antibodies. Thus, we propose that the mechanism by which bound antibodies disrupt the uncoiling of natural fimbria under force is by clamping together layers of the helical filament, thereby increasing their stiffness and reducing their resilience during fluid flow. In addition, we propose that antibodies tangle fimbriae via bivalent binding, i.e., by binding to two individual fimbriae and linking them together. Use of antibodies to disrupt physical properties of fimbriae may be generally applicable to the large number of Gram-negative bacteria that rely on these surface-adhesion molecules as an essential virulence factor. IMPORTANCE Our study shows that the resiliency of colonization factor antigen I (CFA/I) and coli surface antigen 2 (CS2) fimbriae, which are current targets for vaccine development, can be compromised significantly in the presence of antifimbrial antibodies. It is unclear how the humoral immune system specifically interrupts infection after the attachment of enterotoxigenic Escherichia coli (ETEC) to the epithelial surface. Our study indicates that immunoglobulins, in addition to their welldocumented role in adaptive immunity, can mechanically damage the resilience of fimbriae of surface-attached ETEC, thereby revealing a new mode of action. Our data suggest a mechanism whereby antibodies coat adherent and free-floating bacteria to impede fimbrial resilience. Further elucidation of this possible mechanism is likely to inform the development and refinement of preventive vaccines against ETEC diarrhea.KEYWORDS pili, IgG, vaccine, CFA/I, CS2, optical tweezers

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Structure and function of enterotoxigenic Escherichia coli fimbriae from differing assembly pathways

Cited by 26 publications

References 52 publications

Biomechanical and Structural Features of CS2 Fimbriae of Enterotoxigenic Escherichia coli

Biomechanical and Structural Features of CS2 Fimbriae of Enterotoxigenic Escherichia coli

Animal EnterotoxigenicEscherichia coli

Antibodies Damage the Resilience of Fimbriae, Causing Them To Be Stiff and Tangled

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